The full content of Annals is available to subscribers

Copyright in the material you requested is held by American College Of Physicians
(unless otherwise noted). This email ability is provided as a courtesy, and by using
it you agree that that you are requesting the material solely for personal, non-commercial
use, and that it is subject to ACP's Conditions of Use.
The information provided in order to email this topic will not be used to send unsolicited
email, nor will it be furnished to third parties. Please refer to
American College Of Physicians'sPrivacy
Policy for further information.

Design:Multicenter, randomized, placebo-controlled trial. Randomization was computer-generated, and participants were allocated to trial groups by using sequentially numbered study drug containers. Patients, caregivers, and those who assessed outcomes were blinded to treatment assignment.

Setting:14 anticoagulant therapy clinics in Canada, the United States, and Italy.

Results:56 patients (15.8%) in the vitamin K group and 60 patients (16.3%) in the placebo group had at least 1 bleeding complication (absolute difference, âˆ’0.5 percentage point [95% CI, âˆ’6.1 to 5.1 percentage points]); major bleeding events occurred in 9 patients (2.5%) in the vitamin K group and 4 patients (1.1%) in the placebo group (absolute difference, 1.5 percentage points [CI, âˆ’0.8 to 3.7 percentage points]). Thromboembolism occurred in 4 patients (1.1%) in the vitamin K group and 3 patients (0.8%) in the placebo group (absolute difference, 0.3 percentage point [CI, âˆ’1.4 to 2.0 percentage points]). Other adverse effects were not assessed. The day after treatment, the INR had decreased by a mean of 1.4 in the placebo group and 2.8 in the vitamin K group (PÂ < 0.001).

Limitation:Patients who were actively bleeding were not included, and warfarin dosing after enrollment was not mandated or followed.

Conclusion:Low-dose oral vitamin K did not reduce bleeding in warfarin recipients with INRs of 4.5 to 10.0.

Funding:Canadian Institutes of Health Research and Italian Ministry of Universities and Research.

Topics

Figures

Study flow diagram.

Patients were screened from large anticoagulant therapy clinics by using the inclusion and exclusion criteria to assess eligibility. Because of the high throughput of such clinics, the numbers of patients screened, ineligible patients, and eligible but not enrolled patients are unknown. We attempted to enroll consecutive eligible patients; however, on many days, research personnel would not have been able to accommodate all eligible patients because of their number.

Comments

Please read the other comments before posting. Contributors must reveal any conflict
of interest.
Comments are moderated and will appear on the site at the discretion of The American
College of Physicians editorial staff. Please be sure your email address is
updated in your account, otherwise the American College of Physicians will not be
able to contact you about your comment.

* = Required Field

Comment Author(s)* (if multiple authors,
separate names by comma)

Example: John Doe

Affiliation & Institution*

Disclosure of Any Conflicts of Interest*
(applies to the past 5 years and foreseeable future) Indicate any potential conflicts
of interest of each author below, including specific financial interests and relationships
and affiliations relevant to the subject matter or materials discussed in the manuscript
(eg, employment/affiliation, grants or funding, consultancies, honoraria, speakers
bureau, stock ownership or options, expert testimony, royalties, donation of medical
equipment, or patents filed, received, or pending). If all authors have none, check
"No potential conflicts or relevant financial interests" in the box below. Please
also indicate any funding received in support of this work. The information will
be posted with your response.

This is a good study and supports the treatment of supratherapeutic INR with merely holding warfarin. Also it supports the results of the authors'double-blind, placebo-controlled, randomized trial which showed that low dose oral vitamin K is more effective than placebo for the rapid lowering of raised INR values in patients taking warfarin. However in that trial, it was observed that fewer patients given vitamin K had bleeding episodes during the follow-up period than those given placebo.

This study has multiple strengths that minimize bias, however, confounding factors were not evaluated enough to explain why there were increases in major bleeding in the vitamin K group. Such factors include but not limited to: GI diseases that impede fat absorptive mechanisms, the severity of the liver disease and use of drugs that can affect INR potentially. Furthermore; it was noted that vitamin K group has a slightly higher mean INR compared to the placebo group which may not be significant enough to explain such difference.

Conflict of Interest:

None declared

Oral Vitamin K: ACCP Guidelines still apply

Posted on
March 9, 2009

Robert C Pendleton

University of Utah

Conflict of Interest:
None Declared

To The Editor:

We read with interest the article by Dr. Crowther and colleagues evaluating the efficacy of low dose oral vitamin K to correct excessive anticoagulation in patients receiving warfarin. First, the authors should be commended for carrying out such an important and well-designed study in an area that has received little prior attention. Despite warfarin accounting for one of the highest annual rates of ADE-related deaths in the U.S., the management of excessive anticoagulation in a clinical practice setting has received little study.

Although the authors were unable to demonstrate a reduction in bleeding events with oral vitamin K, several important considerations should be mentioned. First, the authors do not discuss the duration warfarin dosing prior to the elevated INR. This may be important as annualized bleeding is 2-fold higher in the first month of warfarin therapy (1) and as such, outcomes may be different during the early period of warfarin management. Second, there was no mention of other potentially important clinical variables which may increase an individual's bleeding risk in the setting of excessive anticoagulation such as concomitant antiplatelet agents or presence of a structural site prone to bleeding (such as recent surgery) (2). Third, it is important to recognize that this was mostly a study of vitamin K in patients with a modestly elevated INR as 67% of subjects had an INR < 6.0. As the overall study was underpowered to detect benefits of low dose vitamin K in reducing major bleeding, this is an even greater potential issue for those with INR >6.0.

With these caveats in mind, the conclusions and recommendations of the 2008 American College of Chest Physicians' (ACCP) Evidence-based Guidelines for the management of patients with an INR in the range of 5 to 9 are still prudent. Specifically, practitioners have a choice of either omitting 1-2 doses of warfarin or administering low dose oral vitamin K, especially if bleeding risk is increased (3). Only with additional high quality studies such as Crowther's will we be able to identify subsets of patients who benefit most from the administration of vitamin K in the setting of excessive anticoagulation on warfarin therapy.

Conflict of Interest:

None declared

Vitamin K: to give or not to give?

Posted on
March 13, 2009

Vittorio Pengo

University of Padova

Conflict of Interest:
None Declared

Dear Editor,

We read with interest the study from Crowther et al. (1) published in the March issue of the Annals of Internal Medicine. On one hand we truly appreciated the attempt to put some order on the way overanticoagulated patients should be managed, on the other hand we remain concerned as conclusions would imply a change in a consolidated treatment policy applied in many Thrombosis Centers in Italy. Since the publication of our first work in the field (2) we usually give oral vitamin K to nonbleeding patients with INR>5. In a recent retrospective study (3), we reported on our 10 years experience in 1043 events of overanticoagulation (INR 5-10) treated with 2 mg oral vitamin K. This approach was associated to a very low incidence of bleeding as only 1 major bleeding (secondary to interventional maneuver) occurred during 30-days follow up (0.1%; 95% CI, <0.01 to 0.60). Our protocol is different from that used by Crowther and colleagues: we use more vitamin K in patients with slightly different levels of overanticoagulation, different pharmaceutical form of the administered drug (in solution) with its prompt administration at the time of INR determination. Despite treatment, 10% of the patients were still overanticoagulated the following day. Our results make us hesitant in changing our policy according to the conclusions from Crowther and colleagues. Data from the concurrent trial the authors are conducting (in patients with INR>10) may help in understanding the potential value of vitamin K in treating overanticoagulated patients. It will be interesting to compare these results with those from an analogue study we conducted (4) on 105 patients showing that 3 mg oral vitamin K is safe with no major bleeding events reported over 30 days.

Conflict of Interest:

None declared

The clinical use of Vitamin K

Posted on
March 15, 2009

Yu Han

Xijing Hospital, Fourth Military Medical University

Conflict of Interest:
None Declared

To the editor:

We read with great interest the excellent paper by Dr Crowther MA and colleagues (1), in which the authors drew a conclusion that low-dose oral vitamin K did not reduce bleeding in warfarin recipients.

Although the study was potentially clinically directive, we would like to express 2 concerns. First, the mean age of patients were over 65 years, which left clinicians with a dilemma. We assumed that the practice of excluding young patients from clinical trials limited the application of the trials' findings and should be reviewed. Second, not included in the report was a discussion about initiating and monitoring vitamin K use, or about potential risks, which might be unique among these patients. It was well known that the adverse events associated with vitamin K were dependent on the dose and route of administration. We suggested the development of treatment protocol to optimize safety.

Conflict of Interest:

None declared

Vitamin K to correct excessive anticoagulation

Posted on
March 24, 2009

P Dileep Kumar

Port Huron Hospital

Conflict of Interest:
None Declared

The paper by Crowther and colleagues (1) carries a slightly misleading title. Their study addresses only the patients with an international normalized ratio (INR) between 4.5 and 10 who are not bleeding. Since all bleeders were self excluded from their study, they are not able to comment on the efficacy of low dose Vitamin K to treat bleeding complications in any given patient with prolonged INR.

It is also hard to conceive that the effect of low dose Vitamin K might persist as long as 90 days. Several dietary constituents have significant amounts of Vitamin K (For example, 1/2 cup each of brussels sprouts, broccoli and cauliflower contain 460, 248 and 150 micrograms of Vitamin K respectively). This amount should be sufficient to override any effect of a single administration of low dose Vitamin K.

Based on their data, the Day 7 bleeding events show a trend towards improvement in the Vitamin K group. Could a higher dose of Vitamin K such as 2.5 mg be effective in improving the outcome?

Conflict of Interest:

None declared

Let's Keep Our Eye on the Ball

Posted on
April 3, 2009

Ayad Jindeel

No Affiliation

Conflict of Interest:
None Declared

The article by Crowther et al. (1) raised an important management question regarding a common clinical problem: what do we do with patients who are not bleeding but have prolonged INR (4.5-10) while taking warfarin?

Although the study showed administering 1.25mg oral vitamin K to be significantly more effective in decreasing INR to the therapeutic range than just withholding one dose of warfarin, the conclusion of the study was that "low-dose vitamin K did not reduce bleeding in warfarin recipients with INR of 4.5-10". There were 34 (10.1%) patients in the placebo group vs. 136 patients (41.6%) in the vitamin K group that had an INR between 2.0 and 3.0 (P < 0.001). (1)

So why the contradictory results?

First, participants from at least two centers did not receive the study medication close to the time of initial INR determination because the INR tests were done outside the clinical centers where the patients were treated, and because of the need to consent the patients by phone and the need to ship the study medication to the enrolled patients. Since INR testing is very dynamic, and delays up to 24 hours could significantly change those results, this could lead to overestimation or underestimation of the patients' real INR at the time of receiving the study medication, and potentially could be a reason for the negative result of this study.

Second, although we agree with the authors about the importance of longer follow up (1 month and 3 month), early bleeding risk is the most relevant issue because most of the oral vitamin k effect is within 24 hours. Consequently, the maximal potential benefit of oral vitamin K is expected in the first few days after the patient receives vitamin k for excessive prolongation of INR secondary to warfarin therapy.

In another study of 105 patients with INR > 6, there were 5 major bleeding events; two were delayed on day 12 and day 14. "Both had symptoms referable to bleeding the week before hospital admission" and both had prolonged INR values on hospitalization of 3.1 and 3.3 despite the time lapse. (2)

The authors should provide the timing of all bleeding events with accompanied INRs after randomization. If bleeding happened in a patient in whom the INR did not become within the therapeutic range, then there are many possible explanations, like noncompliance and/or inadequate dose, rather than lack of efficacy. Until more data is obtained to allow making a more substantiated conclusion, we recommend following the ACCP guidelines in the management of this clinical problem. (3)

In their recent study of supratherapeutic warfarinization management with or without vitamin K (1), Crowther et al. use flawed methodology to arrive at what may be an apocryphal conclusion, which is that vitamin K therapy has no role in managing high-INR patients.

The study utilizes a commercially unavailable vitamin K preparation. The pharmacokinetics and effectiveness of this vitamin K preparation have not been clinically validated.

Confronted with overwarfarinization, clinicians explore recent relevant events, exclude patient dosing errors, consider vitamin K and, most important, dose-modify warfarin. The authors attempt to "control" for dose adjustment by simply blinding us to it. We are given no specific parameters used by practitioners in the trial as regards warfarin dosing. We are thus asked to accept the conclusions of a trial whose methodology has an element of nihilism.

The authors agree that patients who received vitamin K in this trial displayed more rapid corrective moves in INR than those who received placebo. Since the warfarinization regimen was left to clinician judgement, and was not followed after patient enrollment in the study, we cannot help but wonder if clinicians elected less warfarin dose-reduction when the INR had displayed the more-rapid correction in the vitamin K-treated arm. This could easily account for the overall similarity in major bleeding events between the two study arms (which the study is underpowered, in fact, to determine).

For patients with INR 4.5-6.0 during the first seven days of the trial, 12 patients in the vitamin K group experienced bleeding, while 22 placebo-treated patients bled. For patients with INR 6.1 or higher, the lack of a major difference in bleeding events between the arms really just represents the severity of their anticoagulation; in such patients, 1.25 mg vitamin K may be too low a corrective dose. Since the INR for warfarizined patients does not budge until vitamin K-dependent factors in the tissue factor pathway fall to at least 15% of normal values, an INR of 6.0 represents profound anticoagulation.

Groopman and Hartzband recently wrote about the importance of blending deliberative and intuitve decision-making for good patient care (2). We note this in the overall context of about one-seventh of patients in either arm having at least one bleeding complication, an event rate that seems high. Given the lack of association of vitamin K administration with thrombotic events, we view low-dose vitamin K as an appropriate treatment strategy for certain overwarfarinized patients.

Conflict of Interest:

None declared

Vitamin K for warfarin coagulopathy

Posted on
May 22, 2009

Mark A Crowther

McMaster University

Conflict of Interest:
None Declared

Dear Sir/Madam

Our study found that low dose oral vitamin K does not reduce bleeding in asymptomatic patients who present with INR values between 4.5 and 10.0 (1). Thus, one should not recommend vitamin K to patients such as those we enrolled if one's intent is to reduce bleeding.

The INR fell more rapidly in patients allocated to vitamin K, consistent with the pattern we have observed in prior studies. This INR decrease confirms that the formulation used in the present study was effective (2). Similarly, our decision that we would not mandate how warfarin was given after study drug administration was taken only after extensive discussion. We agree with Dr. Swaim that patients whose INR decreased quickly (whether they were allocated to receive vitamin K or placebo) probably undertook less dramatic dose-reductions of warfarin. We contend that such a warfarin dose adjustment is not only appropriate but also reflects routine clinical practice. Thus our study represents the best estimate of the efficacy (or lack thereof) of vitamin K in the "real world."

We acknowledge that an INR value (and the coagulant potential of the blood) could change between the time of measurement and the administration of study drug several hours later. However, this delay had no effect on the observation that the rate of major hemorrhage at 7 days among the placebo-treated patients was low "“ a finding consistent with other studies (3,4). Furthermore it reflects that way that vitamin K is given in the "real world" where the majority of patients have an INR drawn in a community laboratory, are found to have an elevated INR and are called to make arrangements for vitamin K administration hours later.

Larger doses of vitamin K may have produced larger INR corrections and thus may have reduced bleeding; however over-correction of the INR with an attendant risk of thrombosis would then be a consideration. Our choice of dose was based on our prior publications and the fact that the 1.25 mg dose was Â¼ of a standard sized vitamin K tablet available in the United States. However, we cannot rule out the possibility that larger doses (or other formulations) of vitamin K might have reduced bleeding, or that they might have increased thrombosis.

We welcome Dr Pengo's comments as he and his research group have done much of the seminal work in this area (5). However, the observational data he presents in his letter lacks a comparator arm and thus conclusions about relative efficacy cannot be drawn.

(3) Witt DM, Humphries TL. A retrospective evaluation of the management of excessive anticoagulation in an established clinical pharmacy anticoagulation service compared to traditional care. Journal of Thrombosis and Thrombolysis 2003 Apr;15(2):113-8.

Conflict of Interest:

As indicated in the article

Oral Vitamin-K for high INR: Did we really get the answer?

Posted on
June 2, 2009

Mahmoud A Moawad

Harvard Vanguard Medical Associates

Conflict of Interest:
None Declared

In the March 3, 2009 issue, Crowther et al reported that 1.25 mg single dose of vitamin-K has no value in reducing future bleeding in warfarin recipients with INR 4.5-10.0 who were not bleeding (1). In this RCT, they enrolled 724 patients in both arms. INR decreased in the vitamin-K group as expected, but there was no difference in bleeding events at 90 days (primary outcome), nor the rates of thrombosis or death as secondary outcomes. Ad-hoc analysis performed at days 30 and 7 showed similar results.

What does this mean for the practicing clinician? Are we overusing Vitamin-K? Is it a dose issue?

We believe that this article provides little guidance in day-to-day decisions on patient management in situations when INR rises well above therapeutic range, since the bleeding risks of patients was not used as a guiding principle in directing their care. In our practice, we base our recommendation regarding use of vitamin K not only on the absolute level of INR, but also on the underlying bleeding risk of the patient. In the study, bleeding risks such as previous bleeding event, renal insufficiency and cancer were comparable in both groups. However, other known bleeding risks, such as age 65, recent MI, hematocrit <30%, DM (2-5) and concurrent use of antiplatelet agents were not considered, and the decision to treat did not depend on the presence or absence of any of these factors.

Second, the very small number of complications occurring in the study makes the possibility of type-II error very high. Age may have been a confounding factor, as 10 out of 13 major bleeding events were observed in patients older than 70 years. Perhaps the age of the patient, regardless of the treatment arm, was the determining factor.

Third, many clinicians would use higher doses of vitamin K than the 1.25mg dose in the study, especially in patients at the higher end of INR range with high risk of bleeding and low risk of thrombosis.

Finally, the range of inclusion for treatment, beginning at an INR of 4.5, seemed arbitrary and too low. In the absence of actual bleeding, few clinicians would use vitamin K to treat a patient with an INR of 4.5.

The study very clearly and appropriately reminds us that treating all patients with INR elevations with vitamin K may not make sense. However, we need further studies to determine specific patient groups that should or should not receive vitamin K in these situations. This work should include separation of treatment groups based on bleeding risks, and also consider different vitamin K dosing based on the INR elevation, bleeding risk of the patient, and perhaps other clinical factors (such as reason for INR elevation).

Clinical Slide Sets

Terms of Use

The In the Clinic® slide sets are owned and copyrighted by the American College
of Physicians (ACP). All text, graphics, trademarks, and other intellectual property
incorporated into the slide sets remain the sole and exclusive property of the ACP.
The slide sets may be used only by the person who downloads or purchases them and
only for the purpose of presenting them during not-for-profit educational activities.
Users may incorporate the entire slide set or selected individual slides into their
own teaching presentations but may not alter the content of the slides in any way
or remove the ACP copyright notice. Users may make print copies for use as hand-outs
for the audience the user is personally addressing but may not otherwise reproduce
or distribute the slides by any means or media, including but not limited to sending
them as e-mail attachments, posting them on Internet or Intranet sites, publishing
them in meeting proceedings, or making them available for sale or distribution in
any unauthorized form, without the express written permission of the ACP. Unauthorized
use of the In the Clinic slide sets will constitute copyright infringement.